P326: A DUAL ROLE FOR PSIP1 IN T-ALL
Authors: Lisa Demoen, Filip Matthijssens, Lindy Reunes, Zeger Debyser, Steven Goossens, Pieter Van Vlierberghe
Journal: HemaSphere (2023)

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by the diffuse infiltration of malignant T-cell progenitors in the bone marrow. Currently, the cure rates have augmented to 80% for pediatric and 60% for adult T-ALL cases due to modern intensified chemotherapy treatments. Unfortunately, these cure rates come at the cost of severe side effects and current therapy still provides a poor outcome for primary therapy-resistant or relapse cases. Therefore, there is an urgent need for the identification of key drivers and pathways in T-ALL to develop targeted and less toxic therapies. PSIP1, a histone mark reader, was primarily found as a dependency factor in MLL-rearranged AML, which was dispensable for normal hematopoietic development, making it an interesting therapeutic target. Nevertheless, the identification of inactivating mutations and deletions in T-ALL patients, is rather an indication that PSIP1 can also serve as a tumor suppressor in certain contexts. Aims: To determine the role of PSIP1 in tumor initiation and maintenance in T-ALL, we studied the effect of loss of PSIP1 by utilizing several different T-ALL mice models and human cell lines. Methods: To identify the role of PSIP1 during tumor initiation, we crossed a conditional Psipfl/fl knock-out mouse model with two different spontaneous T-ALL mouse models. On the other hand, to unravel the consequences of losing PSIP1 expression during tumor maintenance a proliferation competition assay was performed and RNA-seq profiling was used to identify downstream targets of PSIP1. Results: A conditional Psipfl/fl knock-out mouse model was crossed with two different spontaneous T-ALL mouse models, namely the Notch1 independent Lck-Cretg/+ Ptenfl/fl model and CD2-Lmo2tg/+ transgenic model, which can give rise to ETP-like or Notch1 dependent murine T-ALL tumors. The loss of Psip1 was shown to significantly accelerate T-ALL development in both models, with a p-value of 0.0156 and <0.0001 respectively. RNA-seq profiling was conducted on tumors derived from both models. Interestingly, in contrast with the role of PSIP1 loss in tumor initiation, the loss of PSIP1 expression impaired cell proliferation in multiple human and murine T-ALL cell lines. Lastly, COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, was found to be significantly downregulated upon PSIP1 knock-down. Furthermore, losing COX20 expression led to a similar impairment of proliferation in these cell lines. This indicates that the downregulation of COX20 might be driving the observed impaired proliferation upon PSIP1 loss in T-ALL cell lines, which is currently being further confirmed by rescuing the proliferation impairment by PSIP1 loss by overexpressing COX20. Summary/Conclusion: Altogether, these data indicate that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance. Its dispensability for normal hematopoiesis and its dependency role during tumor maintenance, illustrate the potential of PSIP1 as a therapeutic target in T-ALL.Keywords: T-ALL, Epigenetic, Transgenic mice